NCCN Clinical Practice Guidelines in Oncology: 2014 Updates

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William Gradishar, MD

Elizabeth A. Kvale, MD

Andrew D. Zelenetz, MD, PhD

John C. Byrd, MD

Kenneth C. Anderson, MD

Leora Horn, MD, MSc

John A. Thompson, MD

Peter R. Carroll, MD, MPH

Andrew J. Vickers, PhD

At the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN), held recently in Hollywood, Florida, NCCN Panel members presented updates for several tumor types, briefly summarized here. For a more complete description of all updates, visit

Breast Cancer Guidelines Incorporate Pertuzumab

The 2014 NCCN Guidelines now recommend the addition of pertuzumab (Perjeta) to a number of regimens in both the adjuvant and metastatic settings for HER2-positive disease, according to
William Gradishar, MD, of Northwestern University and the Robert H. Lurie Comprehensive Cancer Center, Chicago.

The Panel noted, “Considering the unprecedented improvement in overall survival in the metastatic setting and the significant improvement in pathologic complete response seen in the neoadjuvant setting, the NCCN Panel considers it reasonable to incorporate pertuzumab in … adjuvant regimens, with duration similar to that used in the neoadjuvant setting, if the patient did not receive pertuzumab as part of neoadjuvant therapy.” Pertuzumab may also be part of neoadjuvant treatment in patients with ≥ T2 or ≥ N1 disease.

The preferred adjuvant foundation is doxorubicin/cyclophosphamide followed by paclitaxel with trastuzumab (Herceptin), with pertuzumab a possible addition. In metastatic disease, the triplet of pertuzumab, trastuzumab, and docetaxel is the only category 1 option listed, based on a significant improvement in both progression-free and overall survival, compared with trastuzumab/docetaxel. Pertuzumab added to docetaxel/carboplatin/trastuzumab is also a preferred regimen, and paclitaxel can be used in place of docetaxel in these triplets. The combination of paclitaxel/bevacizumab (Avastin) remains in the Guidelines, but the Panel added a footnote to emphasize that an overall survival benefit has not been demonstrated.

The Guidelines now include paclitaxel plus trastuzumab as an option for patients with low-risk, HER2-positive stage I tumors. In addition, the Guidelines have updated the principles for HER2 testing to be consistent with those of ASCO, and have added exemestane plus everolimus (Afinitor) to postmenopausal endocrine therapy regimens for systemic disease.

Cancer Survivorship Guidelines Address Two Common Side Effects

The NCCN Survivorship Guidelines were expanded to include a new section on cancer-associated cognitive impairment and a greater focus on chemotherapy-induced peripheral neuropathy in the adult cancer pain section. With growing awareness of the late effects of cancer treatment, the NCCN Panel felt it was time to emphasize these topics.

Susan G. Urba, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, presented recommendations for assessing and managing peripheral neuropathy. Data support the use of antidepressants and opioids, often in combination, she said.

Elizabeth A. Kvale, MD, of the University of Alabama at Birmingham Comprehensive Cancer Center, presented the inaugural guidelines for cognitive impairment, a field that is still struggling from a lack of evidence.

New Section on Cognitive Impairment

The Guidelines acknowledge that cancer and its treatment can disrupt “normal” cognitive function and affect function and quality of life. Of 21 longitudinal studies in breast cancer, 16 have shown that cancer-associated cognitive impairment, particularly verbal ability and thought processing, affects 20% to 30% of patients. This is usually transient but persists long-term for a subset of patients.

The NCCN Guidelines recommend targeted neuropsychological testing and limit neuroimaging recommendations to those patients determined to be at high risk for central nervous system disease. Growing evidence suggests that structural and functional changes underlie the experience. Patients who present with symptoms should also be screened for potentially reversible contributing factors. Unfortunately, evidence-based treatments are lacking, but the NCCN Guidelines describe some patient-centered interventions.

Chemotherapy-Induced Peripheral Neuropathy

At least 20% of patients develop peripheral neuropathy as a result of chemotherapy. While the NCCN Guidelines have long addressed this side effect, the expanded section focuses on long-term cancer survivors, many of whom have persistent pain.

The first line of treatment is antidepressants (especially duloxetine) and anticonvulsants (gabapentin and pregabalin), combined with opioids when pain is severe or refractory. Other recommended interventions include topical agents such as 5% lidocaine patch (usually best when combined with an opioid, antidepressant, and/or anticonvulsant).

Dr. Urba emphasized the need for psychosocial support as well. “These patients may be on lifelong medication, and they should learn coping skills,” she said.

Updates in Non-Hodgkin Lymphoma

Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, reviewed the updates to the NCCN Guidelines for diffuse large B-cell lymphoma and presented the inaugural guidelines in T-cell lymphomas for primary cutaneous CD30-positive lymphoproliferative disorders and large granular lymphocytic leukemia.

Under the diagnosis section of the Diffuse Large B-cell Lymphoma Guidelines, the immunohistochemistry panel was modified to include the MYC gene, which is now considered to be essential in the evaluation of these tumors. Some 5% to 10% of diffuse large B-cell lymphomas harbor a MYC oncogene rearrangement, which is associated with worse outcomes.

Dr. Zelenetz said the Panel “revisited and keeps revisiting the role of imaging in [diffuse large B-cell lymphoma] as new data emerge.” In monitoring early-stage patients who achieve a clinical response, the updated Guidelines state that repeat computed tomography scanning should not be done routinely but only as clinically indicated—a change that reflects the limited utility of surveillance imaging in patients with localized disease.

The debate about the optimal first-line therapy for diffuse large B-cell lymphoma is reflected in the 2014 Guidelines, which list three effective options for primary mediastinal B-cell lymphoma: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) followed by radiotherapy, DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, rituximab), and R-CHOP followed by ICE (ifosfamide, carboplatin, etoposide) with or without radiotherapy.

For first-line therapy in patients with poor left-ventricular function, the attenuated immunotherapy regimen R-mini-CHOP, which contains a decreased dose of CHOP and a conventional dose of rituximab for elderly patients, has been added as an option for patients older than age 80 with comorbidities.

Inaugural Guidelines in T-cell Lymphomas

New Guidelines were issued for the two rare primary cutaneous CD30-positive tumors—anaplastic large cell lymphoma and lymphomatoid papulosis—and for T-cell large granular lymphocytic leukemia.

The treatment algorithm in the NCCN Guidelines for primary cutaneous CD30-positive T-cell lymphoproliferative disorders hinges on the presence or absence of symptoms. For lymphomatoid papulosis patients who are symptomatic and have extensive lesions, methotrexate, phototherapy, systemic retinoids, and topical steroids are listed as treatment options. For anaplastic large cell lymphoma, the treatment pathways diverge depending on whether the lesions are solitary, where surgical excision with or without local radiotherapy is recommended, or multifocal, where methotrexate is the preferred treatment, although radiotherapy, systemic retinoids, pralatrexate (Folotyn), and observation (if asymptomatic) are all listed as options. Most outcomes are good, he said.

T-cell large granular lymphocytic leukemia also follows a typically indolent course. Diagnosis requires peripheral blood smear analysis for cytology, flow cytometry on peripheral blood, bone marrow aspirate and biopsy, and adequate immunophenotyping. Indications for therapy include severe neutropenia, moderate neutropenia with recurrent infections, symptomatic or transfusion-dependent anemia, autoimmune disorders associated with T-cell large granular lymphocytic leukemia, and B symptoms.

As with the primary cutaneous CD30-positive lymphoproliferative disorders, treatment of T-cell large granular lymphocytic leukemia depends on the presence or absence of symptoms, with observation considered reasonable for asymptomatic individuals. In patients with symptoms, first-line choices include methotrexate, cyclophosphamide, and cyclosporine, with or without corticosteroids.

New Standard of Care in Chronic Lymphocytic Leukemia

The treatment of chronic lymphocytic leukemia (CLL) is poised for change, thanks to the development of effective agents targeting the BCR signaling pathway, according to John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

Most CLL patients are diagnosed with early-stage disease, and regardless of risk factors, treatment is initiated only when patients become symptomatic. The choice of regimen is differentiated by age or functional status and by genomic features.

New to the guidelines is the emphasis on del(17p), which is particularly associated with poor outcomes and requires different management. “If you treat any group, this is the one,” Dr. Byrd noted.

The 2014 Guidelines have added the CD20 antibody obinutuzumab (Gazyva)
plus chlorambucil (Leukeran) as a new standard of care, based on the German CLL11 study that found it superior to chlorambucil/rituximab (Rituxan) in multiple endpoints. This regimen is now indicated as first-line treatment in CLL patients without del(11q) or del(17p), both those aged < 70 (with or without comorbidities) and those aged ≥ 70; with del(17p) (any age); and with del(11q) if ≥ 70 or younger with

Similarly, with relapsed disease, treatment is initiated based on symptoms. The NCCN Guidelines list many options, however, with the approval of ibrutinib (Imbruvica), traditional second-line therapies have largely become irrelevant, he pointed out. Ibrutinib, an inhibitor of Bruton tyrosine kinase, and idelalisib, an inhibitor of PI3K-delta, both target the BCR signaling pathway and inhibit B-cell signaling in CLL.

Ibrutinib is listed as a treatment option in relapsed/refractory disease, but idelalisib is still being investigated.

Multiple Myeloma: Support for Continued Treatment

In multiple myeloma, it seems that “more is better,” as studies reported in 2013 support the concept of maintenance therapy after induction and consolidation in newly diagnosed transplant patients, and continued lenalidomide (Revlimid) in nontransplant patients, said Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston.

In transplant candidates, three-drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong progression-free and overall survival, and this is becoming standard practice. In nontransplant candidates, lenalidomide/dexamethasone until progression is now the standard of care. Recent studies have provided the basis for inclusion of bortezomib (Velcade) plus prednisone and bortezomib plus thalidomide (Thalomid) as options for maintenance therapy in the 2014 Guidelines.

Dr. Anderson added that future updates to the NCCN Guidelines will most likely include the oral proteasome inhibitor ixazomib (MLN9708), given the very promising ongoing late-stage trials. “We are now building on the ‘len/dex’ platform, not only by adding the intravenous proteasome inhibitors bortezomib or carfilzomib, but also the oral proteasome inhibitor ixazomib, and the results are very impressive. This all-oral regimen of ixazomib, lenalidomide, and dexamethasone is very active in newly diagnosed myeloma,” he noted.

The 2014 Guidelines also encourage enrollment of patients with smoldering myeloma, defined by IgG ≥ 2g/dL, IgA > 1 g/dL, or Bence-Jones protein > 1 g/24 h in the absence of clinical sequelae including hypercalcemia, renal dysfunction, anemia, or bone disease, onto clinical trials designed to delay or prevent progression to active myeloma requiring therapy.

Relapsed/Refractory Disease

The NCCN Guidelines for relapsed/refractory myeloma include bortezomib, bortezomib plus liposomal doxorubicin, and lenalidomide/dexamethasone as category 1 recommendations. Among the other “preferred regimens” are now carfilzomib as a single agent and pomalidomide (Pomalyst)/dexamethasone. Perhaps the greatest effect will be seen when carfilzomib and pomalidomide are used in combination, Dr. Anderson predicted.

On the horizon are new classes of agents that are demonstrating very impressive gains in remission duration and survival: monoclonal antibodies (elotuzumab, which targets CS1, and daratumumab and SAR650984, which target CD38); an antibody-drug conjugate (indatuximab ravtansine, which targets CD138); histone deacetylase inhibitors (ricolinostat); a kinesin spindle protein inhibitor (filanesib); and an Akt inhibitor (afuresertib).

Non–Small Cell Lung Cancer: Treatment Growing Ever More Targeted

The treatment of advanced non–small cell lung cancer (NSCLC) is increasingly centered on tumor histology and molecular driver mutations, according to Leora Horn, MD, MSc, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Disease progression often occurs as a result of acquired resistance to tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), about half of which involve the second-site T790M mutation. Newer tyrosine kinase inhibitors and combinations of targeted agents appear capable of overcoming drug resistance, including afatinib (Gilotrif), which has been incorporated into the 2014 Guidelines for first- and second-line treatment, and the investigational third-generation tyrosine kinase inhibitors AZD9291 and CO01686.

The ALK/MET inhibitor crizotinib (Xalkori), which is so effective in ALK-positive lung cancer, is being studied in the first-line setting, and another investigational ALK inhibitor, ceritinib, is showing promise in crizotinib-resistant cases.

According to the 2014 NCCN Guidelines, maintenance therapy is an option for select patients with tumor response or stable disease and is not considered the standard of care for all patients. Category 1 options in continuation maintenance therapy include single-agent bevacizumab and single-agent cetuximab (Erbitux) in those with nonsquamous NSCLC who test negative for EGFR mutations and ALK rearrangements.

For primary disease, treatment recommendations have been modified according to nodal status and margin status, and mutational testing recommendations have been refined.

Metastatic Melanoma: A Whole New Ballgame

The NCCN’s list of preferred regimens for metastatic melanoma now tops half a dozen, most being category 1 recommendations. There are eight additional active regimens, a testament to the wealth of new effective agents against what used to be a rapidly fatal disease. The extensive list of treatments forms the key update to the Melanoma Guidelines, according to John A. Thompson, MD, of the Seattle Cancer Care Alliance.

The effective new agents include anti-CTLA4 antibodies, antibodies targeting the programmed death protein and its ligand—anti–PD-1 and anti–PD-L1 agents—and drugs targeting the BRAF and MEK mutations.

The Guidelines list as preferred regimens: single-agent ipilimumab (Yervoy), vemurafenib (Zelboraf), and dabrafenib (Tafinlar) (all category 1), as well as dabrafenib plus trametinib (Mekinist), high-dose interleukin-2 (Proleukin), and enrollment on a clinical trial (not ranked). Among the eight “other active regimens,” only the new MEK inhibitor trametinib earned a category 1 recommendation.

The novel agents are producing durable remissions that can persist for many years. “More and more, we are pulling from this list of preferred drugs rather than using the ‘other’ category,” said Dr. Thompson.

Immunomodulatory and Targeted Agents

With the anti-CTLA4 agent ipilimumab, the survival curve ultimately plateaus, and about 20% of patients are surviving out to 5 years. Enthusiasm is even greater for the anti-PD-1 and anti–PD-L1 agents, to which 30% to 50% of patients with metastatic disease respond, and virtually all responders are alive at 1 year. In combination, these two immunomodulatory classes produce “a striking degree of tumor suppression and responses in the majority of patients,” he observed.

The targeting of the BRAF mutation with vemurafenib and dabrafenib has also changed the treatment landscape, but resistance develops rapidly to these drugs. Much of the resistance is attributed to the action of MEK; therefore, blocking MEK with drugs such as trametinib is now among the recommendations. Combined BRAF and MEK inhibition has proven to be an even better approach, both for efficacy and safety, and this is indicated in the treatment recommendations.

Colorectal Cancer: New Guidelines for Assessing Genetic Risk

New features within the NCCN Guidelines for Detection, Prevention, and Risk Reduction include recommendations for the assessment of high-risk familial and genetic colorectal cancer syndromes. These guidelines now exist under their own cover, paralleling those previously established for the assessment of genetic and familial breast cancer. Prior to 2014, the detection and management of hereditary colorectal cancer fell under the NCCN Colorectal Cancer Screening Guidelines.

The Panel recommends that all colorectal cancer patients be screened for Lynch syndrome. Such screening could be universal (ie, all tumors would be genetically tested) or universal for colorectal cancer patients under the age of 70 and for selected patients older than 70 who meet certain clinical criteria, according to Heather Hampel, MS, CGC, a genetics counselor at The Ohio State University Comprehensive Cancer Center, Columbus.

Universal screening for Lynch syndrome has been a topic of discussion in oncology and gastroenterology circles for several years, but a formal recommendation by the NCCN moves the concept forward, Ms. Hampel said. Almost three-fourths of NCCN centers have begun conducting universal screening for all new colorectal cancer patients.

In the 2014 guidelines, testing for Lynch syndrome is separated into two sections: clinical testing criteria based on personal and family history, and routine tumor testing criteria. Screening the colorectal cancer patient is also a robust cancer prevention strategy among their relatives.

The Panel also refined the recommendations for evaluating, treating, and monitoring familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and colonic adenomatous polyposis of unknown etiology. ■

Disclosure Information

Drs. Kvale and Byrd reported no potential conflicts of interest. Dr. Urba has served on advisory boards, speakers bureaus, and as an expert witness or consultant for Eisai and Helsinn. Dr. Gradishar has served on an advisory board, speakers bureau, and as expert witness or consultant for Bayer HealthCare, Eisai, Genentech, Genomic Health, Myriad Genetic Laboratories, and Onyx Pharmaceuticals. Dr. Carroll has received or participated in clinical research support/data safety monitoring board for Genomic Health, Myriad Genetic Laboratories, National Cancer Institute, and Department of Defense. He has served on an advisory board, speakers bureau, or as an expert witness or consultant for Genomic Health. Ms. Hampel has received or participated in clinical research support/data safety monitoring board for Myriad Genetic Laboratories and University of Washington. Dr. Zelenetz has received or participated in clinical research support/data safety monitoring board for Abbott Laboratories, Boehringer Ingelheim GmbH, Celgene, Cephalon, Genentech, GlaxoSmithKline, Janssen, Millennium, Novartis, Onyx, Infinity, and Seattle Genetics. Dr. Zelenetz has also served on an advisory board, speakers bureau, or as an expert witness, or consultant for Celgene, Genentech, GlaxoSmithKline, Onyx, Bullet Bio Technology, Cancer Genetics, Dr. Reddy`s Laboratories, Emergent Biosolutions, Foundation Medicine, Gilead, Hospira, Roche, and sanofi-aventis U.S. Dr. Horn has received or participated in clinical research support/data safety monitoring board for Boehringer Ingelheim GmbH, OSI Pharmaceuticals. She has also served on an advisory board, speakers bureau,  or as an expert witness or consultant for Bristol-Myers Squibb. Dr. Anderson has served on an advisory board, speakers bureau, or as an expert witness or consultant for Celgene, Millennium, Onyx Pharmaceuticials, Gilead, and sanofi-aventis U.S. Dr. Anderson also reported potential conflicts of interest with Acetylon and OncoPep. Dr. Thompson has received or participated in clinical research support/data safety monitoring board for Bristol-Myers Squibb, Genentech, GlaxoSmithKline, ImClone, Novartis, and Altor Bioscience. He has also served on an advisory board, speakers bureau, or as an expert witness, or consultant for Amgen and Bristol-Myers Squibb. Dr. Vickers is named as a co-inventor on a patent application for a statistical method for predicting the result of a prostate cancer biopsy, commercialized by Opko; Dr. Vickers has stock options in Opko and is due to receive royalty payments from sales of the test.

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